Currently, there is enormous interest in using nanotechnology for a variety of applications, including biomedical ones. Nanoparticles offer many advantages when used for applications such as the delivery of bioactive agents (e.g., DNA, AIDS drugs, immunosuppressants, chemotherapeutics), and drug uptake and degradation (e.g., enzyme encapsulation). In addition, nanotechnology offers considerable potential when applied in other areas, such as agricultural processes (e.g., plant genetics; or controlled fertilizer and pesticide release using sensor technology linked to the payload release mechanism), industrial synthetic processes, and environmental applications (e.g. ultra-effective decontamination and disinfection of areas contaminated with toxic chemicals and/or biotoxins such as bacteria or viruses).
In the biomedical area there are currently a number of viral vector systems under development for gene delivery. Common viral vectors being studied include the adenovirus, adeno-associated virus, retrovirus and herpes simplex virus. However, such systems have a number of disadvantages.
Adenoviruses are non-enveloped particles of size 70 nm containing a linear double stranded DNA of approximately 36,000 base pairs. They are easily prepared with high titers and can infect a wide range of cells, including non-dividing cells. However, adenoviruses cause mild illness in humans and can elicit a strong host immune response. Although recently developed modified adenovirus vectors exhibit a significantly reduced immune response, the viral replication and expression of such vectors are limited.
Adeno-associated viruses have a particle diameter of 20 nm. This small particle size limits the size of the DNA molecule the virus can carry. In addition, adeno-associated viruses are not easily prepared. Particular problems are low production yields and contamination associated with helper virus.
Retroviruses are spherical, enveloped particles 80–100 nm in diameter. Retroviruses have been widely used as vectors for DNA delivery. However, they can only be used to target actively dividing cells. In addition, retroviruses do not accommodate large DNA inserts readily. Major problems also occur in the production of replication competent retrovirus. Such problems typically result in low titers. In addition, biosafety is the major concern for the production of HIV-based vectors.
Herpes simplex viruses are particles of 100 nm diameter containing enveloped, double-stranded DNA virus of approximately 150,000 base pairs. These viruses have a large loading capacity for foreign genes and are able to infect a wide range of cells. In addition, the virus genome remains episomal after infection, thus eliminating the possibility of opportunistic malignant insertional mutagenesis of the host genome. Herpes viruses have been exploited for specific gene transfer trials into the central nervous system. However, herpes viruses can be toxic and inflammatory, although recent advances have decreased their cytotoxicity.
In spite of the availability of replication defective viruses, concerns about the safety and efficiency of such viral vectors has generated interest in the development of nonviral gene transfer systems such as naked DNA, liposome-DNA complexes, and cell-based delivery systems.
In addition, particle-based delivery systems have been investigated for the delivery of oligonucleotides and other bioactive agents. For example, particle-based intravascular delivery of oligonucleotides has been proposed for the selective targeting of tumor vascular endothelial cells (Chispin R. Dass, “Particle-Mediated Intravascular Delivery of Oligonucleotides to Tumors: Associated Biology and Lessons from Genotherapy” Drug Delivery, 8: 191–213 (2001)). Microspheres have been proposed as providing the site-specific distribution of drugs to, and minimization of loss from, the target site. By selecting appropriately sized particles, such particles become trapped in the vasculature of selected tissues where they release their drug load in a controlled and sustained manner.
Important factors related to the use of particle-based delivery systems include the particle structure and size; surface properties; biocompatibility including immunogenic properties and the ability to avoid detection by the reticuloendothelial system of the body for variable lengths of time (“stealthiness”); toxicity; biodegradability; and the mechanism and timing of release of the payload from the particle. Other factors, such as the cost of particle formulation and payload loading, the ease of manufacture, and the ability to recover unloaded payload are also important.
Hence, despite the availability of the above systems, there is a continuing need for a new system for the delivery of bioactive agents and other payloads.